S294: MARIBAVIR (MBV) VERSUS INVESTIGATOR-ASSIGNED THERAPY FOR REFRACTORY CYTOMEGALOVIRUS (CMV) INFECTION: SUBGROUPS ANALYSES OF PHASE 3 STUDY BY RESISTANCE STATUS KNOWLEDGE REPORTED BY INVESTIGATORS.
Authors: Rafael F Duarte, Sophie Alain, Roy F Chemaly, Carmen Montoto, Isabel de Castro-Orós, Johan Maertens, Ignacio Tagarro
Journal: HemaSphere (2023)

Background: Refractory CMV infection with or without mutations conferring antiviral resistance is a major cause of morbidity and mortality post-transplant. In the Phase 3 SOLSTICE study (NCT02931539), MBV was superior to ganciclovir, foscarnet, and/or cidofovir (IAT) in the primary efficacy endpoint, achievement of CMV viremia clearance at Week (Wk) 8. Subgroup analyses of the primary endpoint by baseline genotypic resistance to IAT, as determined by the central laboratory, showed a greater proportion of MBV-treated (vs IAT-treated) patients with genotypic resistance met the primary endpoint, and there was a numeric treatment difference between MBV and IAT among patients without resistance. These analyses did not include 9% of the patients in the SOLSTICE study with baseline CMV DNA samples that could not be genotyped at the central laboratory. Here we conduct similar subgroup analyses with resistance data collected from patients’ medical records at the investigator sites instead of from central laboratory results. Aims: This descriptive, exploratory study was carried out to estimate treatment effects using investigator-reported data on resistance to GCV, FOS, and/or CDV. Methods: Patients with a history of resistance to IAT in their medical record, regardless of the timing of the documented resistance were categorized as “with” resistance. Patients categorized as “without/unknown” included those with a documentation of resistance testing where no mutations were found or without documentation of resistance testing. Comparisons of MBV vs. IAT arm primary efficacy endpoint in subgroups thusly defined as “with” and “without/unknown” resistance (Comparison A) were conducted using the Z-test for independent samples. A sensitivity analysis (Comparison B) was conducted excluding patients with resistance status reported by investigator discordant with central laboratory. And lastly, Comparison C was done for the subset of patients where the only resistance information available was that derived by the investigator from the medical record. Results: In this analysis, 46.3% of patients were categorized by investigators as “with” resistance to IAT, 52.3% were categorized as “without/unknown” resistance, and 1.4% had missing data. For Comparison A, in the subgroup of patients with resistance, the primary efficacy endpoint was met by 61.8% of those treated with MBV vs. 26.2% of those treated with IAT. In the subgroup of patients without/unknown resistance, 53.1% of those in maribavir arm vs. 21.4% in IAT arm met the primary endpoint. For Comparison B, when the relevant 15.6% of patients were excluded, the proportions of patients achieving CMV clearance at Wk 8 were in favor of MBV in both subgroups: with resistance: 62.8% in MBV-treated vs 24.1% in IAT treated; without/unknown resistance: 49.5% in MBV-treated vs 26.9% in IAT treated groups treated (Figure). For Comparison C (32 patients), efficacy rates were higher with MBV: 72.2% with maribavir vs 21.4% with IAT. MBV had fewer treatment discontinuations due to TEAEs including neutropenia and acute kidney injury than IAT. Summary/Conclusion: An efficacy benefit of MBV over IAT arm was observed in patients categorized either as with resistance, or as “without/unknown resistance” by investigator sites. The main limitation of these analyses is that the subgroup of patients thus defined as without/unknown resistance may include some with not identified resistance mutations. However, considering as genetic resistance is locally tested in clinical practice, these results may represent a best-possible estimate of MBV efficacy in patients characterized in the real world as not having resistance to IAT. FigureKeywords: CMV, HSCT, CMV infection, Organ transplant